tbuckley/cabot-search huggingface dataset:
SURG-10. PERMANENT CARRIER-EMBEDDED CESIUM-131 BRACHYTHERAPY FOR THE SALVAGE TREATMENT OF PREVIOUSLY IRRADIATED, RECURRENT BRAIN METASTASES
Authors: Brandon Imber, Kathryn Beal, Anne Reiner, Alexandra Giantini-Larsen, Jonathan Yang, David Aramburu-Nunez, Gil’ad Cohen, Cameron Brennan, Viviane Tabar, Robert Young, Nelson Moss
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Salvage of recurrent, previously-irradiated brain metastases (rBrM) is a significant clinical challenge. High local failure is seen following salvage resection without adjuvant re-irradiation, while re-irradiation is associated with high radionecrosis rates. Salvage surgery plus intraoperative Cs131 brachytherapy may offer dosimetric and biologic advantages including improved local control versus observation, with reduced integral brain dose versus re-irradiation. METHODS A prospective registry of consecutively treated patients with post-stereotactic radiosurgery (SRS) rBrM was analyzed. Following resection, cavities were implanted with commercially-available, collagen-matrix embedded Cs131 seeds (GammaTile, GT Medical Technologies) prescribed to 60Gy at 5mm from the cavity. RESULTS Twenty patients underwent 24 operations with Cs131 implantation in 25 cavities. Previous SRS occurred a median of 358d preoperatively (range=56-1334). Median maximum preoperative diameter was 3.0cm (range=1.1-6.3) and enhancing volume was 9.5cm3 (range=0.6-69.7). Gross- or near-total resection was achieved in 60%. A median of 16 Cs131 seeds (range=6-30), with a median activity of 3.5U/seed were implanted. Maximal preoperative diameter and enhancing volume were weakly associated with the number of implanted seeds (correlation coefficients=0.50, 0.41, respectively). There was one postoperative wound dehiscence in a multiply resected and irradiated patient with hydrocephalus. With median follow-up of 1.6 years for survivors, 2 tumors recurred (one in-field, one marginal) resulting in 9.8% 1-year progression incidence (95%CI=0.0-23.2). Radiographic seed migration was identified in 7/25 cavities (28%) on scans ranging from 1.9-11.7 months post-implantation, without clinical sequelae. CONCLUSIONS With &amp;gt;1 year of follow-up, intraoperative brachytherapy with Cs131 implants was associated with a high rate of local control and a favorable toxicity profile. Modest correlation between preoperative tumor geometry and implanted tiles with high associated cost suggests a need to optimize planning criteria. A randomized trial of salvage resection with or without Cs131 is ongoing (NCT04690348) to assess the incremental benefit of brachytherapy.
CTNI-67. DUAL INHIBITION OF POST-RADIOGENIC ANGIO-VASCULOGENESIS BY OLAPTESED PEGOL (NOX-A12) AND BEVACIZUMAB IN GLIOBLASTOMA – INTERIM DATA FROM THE FIRST EXPANSION ARM OF THE GERMAN PHASE 1/2 GLORIA TRIAL
Authors: Frank Giordano, Julian Layer, Sonia Leonardelli, Lea Friker, Christina Schaub, Roberta Turiello, Elena Sperk, Iris Mildenberger, Franziska Grau, Daniel Paech, Torsten Pietsch, Wolf Mueller, Oliver Grauer, Mirjam Renovanz, Ghazaleh Tabatabai, Sied Kebir, Martin Glas, Sotirios Bisdas, Peter Hambsch, Clemens Seidel, Michael Hölzel, Ulrich Herrlinger
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND We recently reported favorable safety, promising clinical efficacy and immunohistochemical indicators of response after radiotherapy (RT) plus escalating doses of the CXCL12-neutralizing RNA-Spiegelmer olaptesed pegol (NOX-A12) for glioblastoma in the German multicenter phase 1/2 GLORIA trial (NCT04121455). Here, we report outcomes after RT plus dual inhibition of vasculogenesis (NOX-A12) and angiogenesis (bevacizumab). METHODS After establishing safety in the monotherapy arm, we enrolled six patients with incompletely resected GBM, ECOG ≤ 2, age ≥ 18 and without MGMT promoter hypermethylation into a pre-planned expansion arm. Patients received standard RT (60 Gy in 30 fractions), continuous i.v. infusions of NOX-A12 (600 mg/week) and i.v. infusions of bevacizumab (10 mg/kg q2w). The primary endpoint was safety. Secondary endpoints included radiographic response, perfusion/diffusion imaging and neurologic performance. RESULTS Dual treatment was well-tolerated and safe. Of all G ≥ 2 AEs (n = 37), two G2 events (5.4%) were deemed related to NOX-A12. There were no dose-limiting toxicities and no treatment-related deaths. Longitudinal NANO assessment revealed stable neurologic functioning in all patients. Five out of six patients achieved partial responses (PRs) as per mRANO in week 9. All PRs remained durable at a median follow up of 5.6 months (range 3.6 to 9.3 months). No progression occurred. The mean best response was -65.9% (-13.3% to -99.9%) for target lesion sums and -92.1% (-76.2% to -100%) for non-target lesion (NTL) sums. In all three patients with NTL at least one lesion disappeared. The mean best change from baseline of the highly perfused-tumor fraction was -84.5% (-51.9% to -100%) and the mean best change of the apparent diffusion coefficient was 20.1% (-24.5% to 59.1%). CONCLUSION Interim data of the ongoing trial confirm the previously established safety profile of NOX-A12 and suggest improved efficacy of dual inhibition of post-radiogenic angio- and vasculogenesis by the addition of bevacizumab.
CTIM-19. RANDOMIZED PHASE II OPEN-LABEL STUDY OF NIVOLUMAB PLUS STANDARD-DOSE BEVACIZUMAB VS NIVOLUMAB PLUS LOW-DOSE BEVACIZUMAB IN RECURRENT GLIOBLASTOMA (RGBM): FINAL REPORT
Authors: Manmeet Ahluwalia, Atulya Khosla, Yasmeen Rauf, David Peereboom, Patrick Y Wen, David A Reardon
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Anti-PD1 therapy alone in rGBM is of limited efficacy seen in three randomized trials. VEGF is upregulated proangiogenic growth-factor in GBM that contributes to tumor-associated immunosuppression. Preclinical data suggests a potential dose effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD1 and anti-VEGF is promising approach. METHODS 90 patients with GBM at first recurrence were randomized (1:1) to nivolumab (240 mg IV Q2 weeks) with bevacizumab at standard (10 mg/kg; Arm A) or at low dose (3 mg/kg; Arm B) IV Q2 weeks. Stratification included extent of resection, age, performance-status, and MGMT methylation status. Progression-free survival (PFS) and overall survival (OS) were compared. RESULTS 90 patients (Median age 60.6 years, 67.8% male, median KPS 80) were enrolled between May 2018 and Jan 2020. Patients were followed in median 7.7 months (Range 0.7, 28.2). 35 patients were MGMT methylated and 53 patients were MGMT not hypermethylated and 2 were indeterminate. Overall survival was similar between arm A and arm B (1 year: 41.1 vs 37.7%, p = 0.14), while OS was better for arm A in age &amp;gt; 60 compared to arm B (At 1-year: 46.2% vs 23.8%; Median: 10.6 vs 5.9 months; P = 0.046). OS was not statistically different in the two arms for patients with age ≤ 60 years (At 1-year: 35.6% vs 56.4; Median 8.0 vs 12.4 months; P = 0.90). Most frequent toxicities ( &amp;gt;20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Toxicities in grade 3-4 were hypertension (7.8%), fatigue (5.6) and other non-neurological toxicities including DVT, PE, infection, and abnormal liver function. CONCLUSIONS Overall PFS and OS rates appear similar for nivolumab with either standard or low-dose bevacizumab compared bevacizumab monotherapy. Nivolumab with standard bevacizumab benefits patients older than 60 years old. Biomarkers of response data will be presented.
EXTH-39. BIOMARKER DRIVEN TARGETING OF RECURRENT IDH MUTANT GLIOMA WITH ABEMACICLIB
Authors: Ali Nasser, Lisa Melamed, Hiroaki Nagashima, Hiroaki Wakimoto, Daniel Cahill, Julie Miller
Journal: Neuro-Oncology (2022)

Abstract Despite initial responsiveness to standard treatments like radiation and chemotherapy, IDH mutant gliomas inevitably recur, become more clinically aggressive, and lead to untimely death. The aggressive change in clinical outcome is driven by insensitivity to conventional methods of treatment, necessitating an improved therapeutic strategy at this stage of the disease. Greater than 20% of recurrent IDH mutant gliomas exhibit homozygous loss of CDKN2A, leading to the loss of the endogenous CDK4/6 inhibitor p16 and aberrant signaling through the CDK-RB pathway. We hypothesized that CDKN2A loss leads to enhanced sensitivity to CDK4/6 inhibitors which have been approved for use in a variety of other cancer types. We examined the sensitivity of a panel of patient-derived IDH mutant gliomas with either endogenous CDKN2A loss or CRISPR-mediated gene deletion to treatment with CDK4/6 inhibitors. We observed a correlation between CDKN2A loss and enhanced cytotoxicity following abemaciclib treatment in these glioma models. We have characterized the cell cycle profile following abemaciclib treatment by flow cytometry and western blotting in both sensitive and resistant lines. Further, abemaciclib treatment resulted in significant slowing of tumor growth rate in a subcutaneous patient-derived IDH mutant glioma model. Survival studies in an intracranial model are ongoing. These preclinical results provide foundational data to support a biomarker-driven clinical trial of CDK4/6 inhibitors in patients with recurrent IDH mutant glioma.
CTNI-40. PHASE I TRIAL OF SULFASALAZINE COMBINED WITH STEREOTACTIC RADIOSURGERY FOR RECURRENT GLIOBLASTOMA: STUDY PROTOCOL FOR NCT04205357
Authors: Bente Sandvei Skeie, Sidsel Bragstad, Shahin Sarowar, Maziar Behbahani, Christopher Filippi, Jonathan Knisely, Michael Schulder, Dorota Goplen, Geir Egil Eide, Jan Ingemann Heggdal, Renate Gruner, Per Øyvind Enger
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is one of the most aggressive, radioresistant types of cancer with a dismal prognosis. Sulfasalazine (SAS) has shown tumor selective radiosensitizing properties in preclinical studies. The antioxidant glutathione (GSH) produced at high levels in glioma cells normally protects against radiation injury by scavenging reactive oxygen species produced during radiation therapy (RT). SAS blocks cysteine uptake through the xCT-channel, a rate-limiting step for GSH production. We have previously shown slowing of tumor growth and prolonged survival when SAS was combined with stereotactic radiosurgery (SRS) in vivo compared to either treatment alone. Our hypothesis is that SAS potentiates the efficacy of SRS for recurrent GBM with a low risk of adverse events (AE). The primary end-point is to establish the recommended dose for efficacy testing in phase II/III trials. This phase 1 dose-escalation trial utilizes a standard 3 + 3 design with 3-6 patients per cohort. Patients will be treated with oral SAS (1.5, 3.0, 4.5 or 6.0 g/day) 3 days prior to single session SRS. The SAS-dose will be escalated depending on the absence/presence of toxicity in the previous cohort of treated patients. If more than 1 of 3-6 patients ( ≥ 33 %) is experiencing grade 3 or higher toxicity levels, the study will be terminated. The dose below will be the recommended dose. Toxicity is graded using the Common Toxicity Criteria for Adverse Events (CTCAE) v5.0 recorded the first 30 days. Secondary end-points are assessments of 1) intratumoral GSH production (GSH-spectroscopy), 2) late AE utilizing 11C-MET-MRI-PET 3) changes in KPS/quality of life (FACT-Br), 4) need for steroidal treatment, 5) progression free and overall survival. Novel treatment modalities are urgently needed. This trial will establish the recommended dose for SAS repurposed as a radiosensitizer for a future phase 2/3 trial and may ultimately lead to improvement of current GBM treatment.
NIMG-85. RADIOMIC FEATURES PREDICTIVE OF RESPONSE IN HGG-TARGETING CAR-T THERAPY
Authors: Aleksandr Filippov, Lawrence Shaktah, Chi Wah Wong, Kimberley-Jane Bonjoc, Bassam Shaktah, Russell C Rockne, Christine Brown, Ammar Chaudhry, Behnam Badie
Journal: Neuro-Oncology (2022)

Abstract SIGNIFICANCE Radiomics may improve precision medicine in CAR-T (Chimeric Antigen Receptor T Cell) therapy patient selection. BACKGROUND High-Grade Glioma (HGG) is a heterogenous primary CNS neoplasm with a high recurrence rate and poor outcomes. Many studies are exploring CAR T cells to combat HGG. Radiomic models have shown value in identifying biomarkers predictive of tumor genetics, response, and patient prognosis. In this study, we explore radiomic features derived from four clinical sequences and volumes of edema and enhancing tumor to predict treatment response to the first three doses of CAR-T therapy. METHODS In this IRB-approved phase 1 clinical trial (IRB 13384), patients underwent surgical resection of the tumor and received CAR-T cell therapy. Of the 82 patients accrued, 59 (20 females, median age = 49) completed three cycles of therapy and had 3T field strength MRI scans with minimal imaging artifacts. T1 weighted pre-contrast, T1 weighted post-contrast, T2 weighted, and T2 FLuid Attenuated Inversion Recovery sequences were used to generate 3D and 2D radiomics features. In total 28,541 radiomic features were generated per patient using the images prior to CAR-T administration. Each patient’s response to treatment after three cycles was determined to be either stable disease (29 patients) or progression. The radiomic feature set dimensionality was reduced using Maximum Relevance Minimum Redundancy. 10-fold cross-validation XGBoost was used to determine radiomic features predictive of treatment response with a randomized grid search for hyperparameter tuning. RESULTS Six radiomic features (four shape-based), had high SHapley Additive exPlanations (SHAP)-based importance feature predictive of RANO response with an AUC &amp;gt;0.73. CONCLUSION Despite the limited study size, such imaging-based radiomic models can serve as a potential basis for optimizing clinical trial design through more precise patient screening and providing potential predictive imaging biomarkers of whether a patient will respond to CAR-T cell therapy in HGGs.
QOL-20. PATTERNS AND PREDICTORS OF ANXIETY AND DEPRESSION SYMPTOM TRAJECTORIES IN PATIENTS DIAGNOSED WITH PRIMARY BRAIN TUMORS
Authors: Alayna Ernster, Anjelica Body, Phuong Deleyrolle, Jennifer St Clair, Deborah Sampson, Maryam Rahman, David Tran, Duane Mitchell, Ashley Ghiaseddin, Deidre Pereira
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Patients diagnosed with primary brain tumors (pPBTs) exhibit high psychological distress. This study assessed how symptoms of anxiety and depression change over time in pPBTs and identified factors that may predict patients’ symptom trajectories. METHODS Ninety-nine adult pPBTs completed psychosocial assessments at routine neuro-oncology clinical appointments over 6 to 18 months, with a minimum 8-week interval between assessments. Symptoms of anxiety and depression were assessed with the PROMIS Anxiety and Depression Short-Forms. The prevalence and incidence of patients with clinically elevated anxiety and depression symptoms throughout follow-up were examined, along with the prevalence of patients that experienced clinically meaningful changes in symptoms between follow-ups. Linear mixed-effects models evaluated changes in symptoms over time at the group level and latent class growth analysis (LCGA) evaluated changes in symptoms over time at the individual level. RESULTS At baseline, 51.5% and 32.3% of patients exhibited clinically elevated levels of anxiety and depression, respectively. Of patients with any follow-up data (N = 74), 54.1% and 50% experienced clinically meaningful increases in anxiety and depression scores, respectively. The incidence of moderate to severe anxiety and depression was 15.6% and 8.3%, respectively. There was no significant change in symptoms over time at the group level, but better physical, functional, and brain-cancer well-being predicted significantly lower anxiety and depression symptoms (p&amp;lt; .001). Results from LCGA showcased 5-unique subgroups of patients with distinct anxiety and depression symptom trajectories. CONCLUSION pPBTs commonly experience elevated anxiety and depression. Symptoms of anxiety and depression change in clinically meaningful manners throughout the disease, even in the absence of significant group-level time effects. Routine screening for elevated symptoms is needed to capture clinically meaningful changes in symptoms and identify factors affecting symptoms to intervene.
QLTI-17. PROPHYLACTIC VANCOMYCIN REDUCES OMMAYA RESERVOIR-ASSOCIATED BACTERIAL MENINGITIS: A 12-MONTH PROSPECTIVE STUDY
Authors: Mara Trifoi, Krishana Sichinga, Matthew Levit, Dawit Aregawi, Brad Zacharia, Alireza Mansouri, Michael Glantz
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Intraventricular chemotherapy administered through an Ommaya reservoir (OR) constitutes the mainstay of therapy for adults with leptomeningeal metastases from solid and hematologic malignancies. Unfortunately, OR-associated bacterial meningitis remains a relatively frequent, costly, often morbid, and occasionally fatal complication, limiting the benefit of this approach. We investigated the potential efficacy, cost savings, and toxicity of intraventricular vancomycin co-administered with intraventricular chemotherapy. METHODS Detailed demographic, treatment, and outcome data were collected prospectively between 5/1/21 and 4/30/22 for 63 consecutive patients at our institution who underwent OR placement and subsequent intraventricular chemotherapy, co-administered with 10 mg of intraventricular vancomycin at each treatment. Reservoir-associated bacterial meningitis was defined as 2 consecutive positive cultures from the cerebrospinal fluid of the same organism or 1 positive culture in the presence of any other clinical or laboratory evidence of infection, or signs of infection at the surgical site. RESULTS The infection rate was 0% [95% CI 0-6.75%] among the 63 patients and 0% [0-0.76%] in the 501 consecutive treatments administered over the 12-month study period compared to 10.25% [7.39- 14.0%] in 322 patients and 1.71% [1.22-2.39%] in 1932 treatments over the preceding 5 years. The absolute risk reduction was 10.3% [3.83 - 14.04], p = 0.0049. The number needed to treat was 10 [7-26]. Cost per vancomycin dose was $10.00 ($5,010 over 12 months). The cost of non-surgical treatment of one OR-associated infection is $88,337.70, which translates into a $618,363.90 savings for the estimated 7 patients over 12 months spared an OR-associated infection. Savings were even further increased if OR removal and subsequent replacement was required. The only other covariate associated with (increased) infection risk on multivariable analysis was treatment number. No treatment-associated toxicity was observed. CONCLUSION Prophylactic intraventricular vancomycin eliminated OR-associated infection in patients receiving intraventricular chemotherapy. Dramatic cost savings were achieved without added toxicity.
BIOM-05. THE HER2 FLIP: HER2 AMPLIFICATION OF TUMOR CELLS IN THE CEREBROSPINAL FLUID (CSF-TCS) OF PATIENTS WITH SOLID TUMOR LEPTOMENINGEAL METASTASIS
Authors: Priya Kumthekar, Michael Youssef, Nicholas Blondin, Amir Azadi, David Piccioni, Michael Glantz, Jose Carillo, Akanksha Sharma, Nicholas Avgeropoulos, Sherif Makar, Barbara Blouw, Anna Natasha, Deanna Fisher, Lan Huynh, John Peters, Mariko Matsutani, Edgar Sales, Nathan Sweed, Michael Dugan, Santosh Kesari
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Patients with leptomeningeal metastasis (LM) have limited treatment options and a poor outcome. However, they may benefit from targeted therapy. LM patients with HER2-positive primary breast cancer treated with IT trastuzumab demonstrated clinical benefit (Malani, 2020), and improved PFS (Figura, 2019). HER2 amplification in the primary and metastatic tumors can be divergent. Biocept’s CNSideTM is a CLIA validated test that can detect CSF tumor cells (CSF-TCs) and interrogate those cells with FISH and NGS. We analyzed HER2 amplification on CSF-TCs in LM patients with breast cancer, non-small cell lung cancer (NSCLC) and upper GI cancer. METHODS CSF was collected from patients with suspected or confirmed LM with breast cancer (N =134 patients), NSCLC (Nf28 patients) or upper GI cancer (Nf2 patients). CSF TCs were tested for HER2 amplification by FISH using CNSide. RESULTS HER2 amplification in CSF-TCs was detected in 46% (76/164) of all patients. Of the breast cancer patients, 37% (49/134) flipped HER2 status in the LM tumor, 38% (41/108) switched from a HER2 negative or equivocal primary tumor to HER2 positive CSF-TCs, and 27% (7/26) from a HER2 positive primary tumor to HER2 negative CSF-TCs. For the NSCLC patients, 50% (14/28) showed HER2 amplification on the CSF-TCs. For the upper GI cancer patients, HER2 amplification in CSF-TCs was detected in both patients, one patient had an equivocal HER2 primary tumor and HER2 positive CSF-TCs. CONCLUSION HER2 amplification was detected in a substantial fraction of CSF-TCs from patients with LM from breast, upper GI, and NSCL cancers. This finding may have important therapeutic (justifying the use of intra-CSF trastuzumab), prognostic (HER2 positivity in NSCLC is associated with poorer prognosis and a higher frequency of CNS metastases) and pathophysiologic implications (a potential role of HER2 amplification in the genesis of CNS metastases). Additional investigations are underway.
DDEL-11. DETERMINING THE DOSE OF REGADENOSON MOST LIKELY TO TRANSIENTLY ALTER THE INTEGRITY OF THE BLOOD-BRAIN BARRIER IN PATIENTS WITH GLIOMAS
Authors: Carlos Romo, Benjamin Ellingson, Roy Strowd, Glenn Lesser, Catalina Raymond, Brian Kral, Xiaobu Ye, Serena Desideri, Joy Fisher, Stuart Grossman
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The blood brain barrier (BBB) is a major obstacle to the delivery of chemotherapy to the CNS. Regadenoson is an FDA approved adenosine A2 agonist used for cardiac stress tests. In murine models, it transiently increases BBB permeability to a 70KD dextran. This multi-institutional, NIH funded, Adult Brain Tumor Consortium trial was designed to discover a dose of regadenoson that substantially increases vascular permeability in normal appearing white matter (NAWM) where drug delivery is particularly challenging. METHODS Adults ages 18-45 with supratentorial gliomas at low-risk for regadenoson complications were recruited (n = 7). One patient was treated at each of seven dose levels (from 0.05 to 1.4 mg) that are known to be safe in humans. The primary outcome measure is change in vascular permeability via dynamic contrast enhanced (DCE) perfusion MRI estimates of Ktrans. The primary outcome measure was a 10-fold higher Ktrans in NAWM than reported in literature (Ktrans &amp;gt; 0.04 min-1). Contrast-enhanced T1 subtraction map estimates of change in contrast enhancement and other measurements in normal brain and non-enhancing tumor were quantified. RESULTS Ktrans measures in NAWM averaged 1.13x10-3 ± 0.44x10-3 (SEM) min-1, lower than the target of 0.04 min-1. Normalized, contrast enhanced T1-weighted MR signal intensity in NAWM increased an average of 74.0 ± 22.4% min-1 (SEM) min-1, which was significantly higher than zero (P = 0.0163). Data available from this limited sample failed to meet the target goal in Ktrans increase or change in contrast enhancing signal intensity. CONCLUSION Administration of regadenoson at seven different doses did not significantly elevate Ktrans for gadolinium in NAWM. This data suggests that single doses of regadenoson are unlikely to substantially increase the delivery of therapeutic agents in non-enhancing brain tissue. This trial design is appropriate for further human testing of other regadenoson schedules and other novel approaches aimed at transiently modifying BBB permeability.